Abstract
We report on the genetic analysis of a Chinese family in which four male patients presented with postlingual progressive hearing loss, associated with distal muscle wasting and unsteady ataxic gait. Using whole exome sequencing, we identified a new pathogenic variant (c.1463C>T, p.Pro488Leu) in the AIFM1 gene, which encodes the apoptosis-inducing factor mitochondrion-associated 1 precursor. AIFM1 is involved in the mitochondrial respiratory chain and cellular caspase-independent apoptosis pathway and has been reported to cause multiple phenotypes including hearing loss. The p.Pro488Leu missense variant segregated with symptoms in the pedigree. It was not found in the dbSNP database, databases of genomes and SNPs in the Chinese population, in 74 patients with sporadic hearing loss, or in 108 normal individuals.We also verified that this AIFM1variant enhanced cell apoptosis rates compared in 293T cells transfected with wild-type AIFM1. Different variations of AIFM1 give rise to different phenotypes in patients, and this is the second reported family with a variant in the C-terminal domain of AIFM1 showing the phenotype of hearing loss and peripheral neuropathy.
Highlights
According to different clinical manifestations, hereditary hearing loss can be divided into non-syndromic (70%) and syndromic (30%) hearing loss
Mutations in the AIFM1 gene, which encodes a flavin adenine dinucleotide-containing, NADH-dependent oxidoreductase resides in the mitochondrial intermembrane space, can cause either non-syndromic or syndromic hearing loss
In this study, using whole exome sequencing, we identified a novel variant (c.1463C>T, p.Pro488Leu) in exon 14 of the AIFM1 gene responsible for the X-linked recessive hereditary hearing loss in a Chinese pedigree
Summary
According to different clinical manifestations, hereditary hearing loss can be divided into non-syndromic (70%) and syndromic (30%) hearing loss. Non-syndromic hearing loss (NSHL) is clinically manifested in symptoms of the auditory system alone, and is not accompanied by other organ or system abnormalities (Alford et al, 2014). Mutations in the AIFM1 (apoptosis-inducing factor mitochondrion-associated 1) gene, which encodes a flavin adenine dinucleotide-containing, NADH-dependent oxidoreductase resides in the mitochondrial intermembrane space, can cause either non-syndromic or syndromic hearing loss. Diseases caused by AIFM1 gene mutations have previously been described as progressive mitochondrial encephalomyopathy Phenotype–genotype comparisons provide insights into the association between different AIFM1 mutations and clinical manifestations, the classification of clinical characteristics caused by different mutations of AIFM1 has hitherto remained elusive (Diodato et al, 2016). A classification of phenotypes associated with different mutations was suggested
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